Prostaglandins have long been known to play an important role in peripheral mechanisms of nociceptor sensitization and hyperalgesia. However, there has been increasing awareness that prostanoids also act centrally, and new evidence suggests that prostaglandins exert their effects in the brain in part by recruiting a brainstem pain-modulating system with links in the midbrain periaqueductal gray and rostral ventromedial medulla (RVM). Our goal is to identify mechanisms through which PGE2 acting supraspinally might gain access to this brainstem descending modulatory system to facilitate nociception. Our approach will involve behavioral pharmacology and single cell recording studies in lightly anesthetized rats. We will focus on the medial preoptic area (MPO) because PGE2 acting in the MPO plays a central role in the hyperalgesia associated with illness, and because we recently demonstrated that PGEa in the MPO recruits the pain modulatory circuitry of the RVM. We will use inactivation studies to determine whether the altered nociception and thermogenesis produced by PGE2 in the MPO are mediated by functionally distinct cell classes in the RVM. We will also use selective prostaglandin E-type receptor agonists to determine if different receptors mediate the hyperalgesic and thermogenic effects of PGEa in the MPO. We will determine whether different RVM cell populations respond to PGE2 applied within the RVM itself, and test whether the pathway(s) from the MPO to the RVM for hyperalgesia and thermogenesis relay in the periaqueductal gray and/or dorsomedial hypothalamus. [unreadable] These studies will provide important insights into the supraspinal actions of PGE2, and into how higher structures such as the MPO influence brainstem pain modulating systems. Knowledge of the mechanisms through which prostaglandins recruit descending control systems will advance our understanding of the neural basis of pain modulation, and should ultimately lead to improved clinical treatment of pain. [unreadable] [unreadable]